Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies
Romain Guièze, Vivian M Liu, Daniel Rosebrock, Alexis A Jourdain, María Hernández-Sánchez, Aina Martinez Zurita, Jing Sun, Elisa Ten Hacken, Kaitlyn Baranowski, Philip A Thompson, Jin-Mi Heo, Zachary Cartun, Ozan Aygün, J Bryan Iorgulescu, Wandi Zhang, Giulia Notarangelo, Dimitri Livitz, Shuqiang Li, Matthew S Davids, Anat Biran, Stacey M Fernandes, Jennifer R Brown, Ana Lako, Zoe B Ciantra, Matthew A Lawlor, Derin B Keskin, Namrata D Udeshi, William G Wierda, Kenneth J Livak, Anthony G Letai, Donna Neuberg, J Wade Harper, Steven A Carr, Federica Piccioni, Christopher J Ott, Ignaty Leshchiner, Cory M Johannessen, John Doench, Vamsi K Mootha, Gad Getz, Catherine J Wu, Romain Guièze, Vivian M Liu, Daniel Rosebrock, Alexis A Jourdain, María Hernández-Sánchez, Aina Martinez Zurita, Jing Sun, Elisa Ten Hacken, Kaitlyn Baranowski, Philip A Thompson, Jin-Mi Heo, Zachary Cartun, Ozan Aygün, J Bryan Iorgulescu, Wandi Zhang, Giulia Notarangelo, Dimitri Livitz, Shuqiang Li, Matthew S Davids, Anat Biran, Stacey M Fernandes, Jennifer R Brown, Ana Lako, Zoe B Ciantra, Matthew A Lawlor, Derin B Keskin, Namrata D Udeshi, William G Wierda, Kenneth J Livak, Anthony G Letai, Donna Neuberg, J Wade Harper, Steven A Carr, Federica Piccioni, Christopher J Ott, Ignaty Leshchiner, Cory M Johannessen, John Doench, Vamsi K Mootha, Gad Getz, Catherine J Wu
Abstract
Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.
Keywords: AMPK; BCL-2; CRISPR/Cas9; chronic lymphocytic leukemia; clonal evolution; drug resistance; genome-wide screen; metabolism; mitochondrion; venetoclax.
Conflict of interest statement
DECLARATION OF INTERESTS
C.J.W. is a co-founder of Neon Therapeutics, Inc and is a member of its scientific advisory board, and receives research funding from Pharmacyclics. R.G., Abbvie (honoraria, travel funds), Janssen (honoraria, travel funds), Gilead (honoraria, travel fund) and Roche (travel funds). J.R.B. serves as a consultant for Abbvie, Genentech, Astra-Zaneca, Janssen, Pharmacyclics, Gilead, Verastem, TG Therapeutics, Sunesis and Loxo and receives research funding from Gilead, Verastem and Sun. J.W.H. is co-founder of Rheostat Therapeutics and is member of its scientific advisory board and is also a member the scientific advisory board of X-Chem, Inc (honoraria). A.G.L. discloses consulting and laboratory research support from AbbVie, Novartis, and Astra-Zeneca; he is an equity-holding co-founder of Flash Therapeutics and Vivid Biosciences. V.K.M. is on the Scientific Advisory Board of Janssen Pharmaceuticals, is a venture partner consultant to 5AM Ventures, and a founder and equity holder in Raze Therapeutics. R.G. and C.J.W. disclose a patent related to this work ((U.S. Provisional Application No. 62/744,081). All other authors declare no competing interest.
Copyright © 2019 Elsevier Inc. All rights reserved.
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Source: PubMed